Gout afflicts more than 8 million U.S. subjects, and is associated with chronic elevation of uric acid (UA) in blood. The incidence of this condition has doubled in the past ten years. When UA exceeds solubility limits, it forms crystals that settle into joints and kidney, causing severe pain, destructive arthritis, and kidney failure. Treatment for chronic gout entails extended—if not lifelong—therapy focused on reducing UA production or increasing its excretion. The standard-of-care is allopurinol, a drug that inhibits xanthine oxidase (XO), a key production enzyme. Launched in 2010, Uloric® (febuxostat; Takeda), has similar activity with an improved safety profile. Xanthine oxidase inhibitors are used as initial therapy in more than 90% of gout patients, but the therapeutic target is achieved in less than 50%. The drugs have multiple side effects and hypersensitivity is common.
Since 2000, rapid advances in the biology of proteins known as transporters have presented an array of new drug targets. The enzyme URAT1 is a high capacity renal transporter that reabsorbs most of the UA that is initially filtered into the urine from the blood by the kidney. Inhibitors of certain urate transporters may prevent such reabsorption and thereby increase UA excretion. Several drugs are now known to inhibit URAT1, including benzbromarone (approved but withdrawn by Sanofi in 2003), probenecid, and lesinurad (AstraZeneca), a drug currently in Phase 3 development.
These drugs are all mono-functional. That is, they inhibit only one of the two equilibrium paths that reduce the levels of UA in blood (i.e., decreased production or increased excretion). Allopurinol is an example of a drug that decreases UA production by inhibiting xanthine oxidase, but it has no effect on renal excretion. As expected, allopurinol does not affect the activity of URAT1 or other renal urate transporters. Benzbromarone, lesinurad and probenecid increase UA excretion (i.e., they promote uricosuria) primarily via inhibition of URAT1, but these agents have no effect on UA production, since they have no substantial effect on xanthine oxidase. Since xanthine oxidase inhibition is the principal and primary form of treatment for hyperuricemia, agents that promote uricosuria are typically used second-line and are commonly employed in combination with xanthine oxidase inhibitors rather than as single-agents.
5-carboxanilide derivatives of barbiturates, including merbarone (5-(N-phenylcarboxamido)-2-thio-barbituric acid) have been evaluated as potential cytotoxic anticancer drugs. Subsequently, it was discovered that clinical treatment with merbarone was associated with a marked reduction of UA levels in blood. Despite these discoveries, the cytotoxic activity of merbarone would completely preclude its use as a treatment for chronic lifelong disorders of UA metabolism, since the safety of such use (primarily its carcinogenic potential) would pose a serious risk to other aspects of human health. Such clinical utility would only be possible if the cytotoxic activity could be chemically dissociated from the various hypouricemic activities. However, no non-cytotoxic (or low cytotoxicity) hypouricemic derivatives of merbarone have yet been reported.
The urinary metabolites of merbarone were initially characterized by a team led by one of the inventors (R. P. Warren, Jr.) (see J. J. Dimaggio, et al., 1990. Cancer Res. 50:1151) and by J. G. Supko, et al. (1991. Drug Metabolism and Disposition. 19:263-273). Three of these metabolites were identified as 4′-hydroxymerbarone[1,2,3,4-tetrahydro-6-hydroxy-2-thioxo-4-oxo-N-(4′-hydroxyphenyl)-5-pyrimidinecarboxamide or 5-(N-(4′-hydroxyphenyl)carbamoyl)-2-thioxobarbituric acid], 2-oxo-desthiomerbarone[1,2,3,4-tetrahydro-6-hydroxy-2,4-dioxo-N-phenyl-5-pyrimidinecarboxamide or 5-(N-phenylcarbamoyl)barbituric acid], and 4′-hydroxy-2-oxo-desthiomerbarone[1,2,3,4-tetrahydro-6-hydroxy-2,4-dioxo-N-(4′-hydroxyphenyl)-5-pyrimidinecarboxamide or 5-(N-(4′-hydroxyphenyl)carbamoyl)barbituric acid]. Several minor metabolites were also found, but were not identified.
There exists a compelling need for new drugs than can reduce UA levels in blood and provide better treatment for patients afflicted by gout. Reduction in UA is universally acknowledged as beneficial for patients with gout and other hyperuricemic disorders, and reduced serum UA is accepted by international drug regulatory agencies (e.g., the U.S. Food and Drug Administration (FDA), the European Medicines Agency (EMA), etc.) as an endpoint for commercial drug approval in these diseases. As previously noted, drugs that can overcome the limited clinical activity of xanthine oxidase inhibitors are available or are currently being investigated, but only as “add-ons” for combination use. Heretofore, the use of a single drug with potent bifunctional activity (i.e., to decrease UA production by inhibiting xanthine oxidase and to increase UA excretion by inhibiting a renal urate transporter) and low toxicity has not been possible. It has now been discovered that certain metabolites of merbarone address each of these needs.